The first step in the pathogenesis of an allergic response is the production of immunoglobulin E (IgE) antibody in response to an allergen. Upon exposure to allergens the B cells of responsive individuals secrete IgE molecules specific to the allergen. IgE molecules bind to the high affinity IgE receptor (FcRI) present on mast cells and basophils. IgE binding activates the release of a variety of vasoactive mediators which promote allergic and inflammatory responses. Activation occurs whenever 2 or more FcRIs are crosslinked via bound IgE molecules that in turn form an aggregate with an allergen molecule. Such aggregation initiates a biochemical cascade which releases histamine and proteases from cytoplasmic granules and leads to the synthesis of prostaglandins, leukotrienes, cytokines and other effectors of the hypersensitivity response.
Mast cells and basophils accumulate at sites of inflammation and, upon activation, secrete haemopoietic growth factors such as granulocyte/macrophage colony-stimulating factor, interleukin-3, and interleukin-6. These factors propagate the inflammatory response by recruiting, priming, and activating inflammatory cells such as neutrophils, macrophages and eosinophils. The activated cells accumulate in areas of ongoing inflammation, tumor invasion, angiogenesis, fibrosis, and thrombosis. The IgE-dependent activation of cells via FcRI results in an inflammatory response directed towards local tissue defense, tissue maintenance and remodeling, and immunoregulation (Gagari, E. et al (1997) Blood 89:2654-2663).
IgE binding to the FcRI activates kinases which are bound to the receptor under resting conditions. When the receptor is phosphorylated, it recruites and activates signaling molecules, such as syk, which activate downstream effector molecules. The phosphorylated receptor activates sphingosine kinase, which contributes to calcium mobilization in mast cells. Other early events induced by FcRI aggregation are the activation of the tyrosine kinases, Lyn and Syk, and the tyrosine phosphorylation of cytoplasmic molecules including phospholipase C-.gamma.. Phosphorylated phospholipase C-.gamma. hydrolyses phosphatidylinositol 4,5-bisphosphate and liberates inositol 1,4,5-trisphosphate and diacylglycerol. The latter mobilizes Ca2+ from intracellular and extracellular sources and activates protein kinase C (Paolini, R. et al. (1991) Nature 353: 855-858; and Beaven, M. A. and Baumgartner, R. A. (1996) Curr. Opin. Immunol. 8:766-772).
The FcRI is a tetrameric complex composed of an .alpha.-chain, a.beta.-chain, and a dimer of identical disulfide-linked .gamma.-chains. IgE molecules binds through their Fc region to the FcRI-.alpha. subunit with a 1:1 stoichiometry. The .beta.- and .gamma.-chains of FcRI are required for the insertion of the receptor chains into the membrane and for signal transduction upon activation of the receptor complex by IgE binding. The FcRI .beta. subunit and related molecules such as the HTm4 and CD20 proteins, contain four transmembrane domains and both the amino and carboxy terminus are located in the cytoplasm. The human HTm4, CD20, and FcRI genes map to chromosome 11q12-13.1 and the murine homologue for CD20, Ly-44, and the murine FcRI .beta. subunit map to the same region of murine chromosome 19. Genetic linkage studies indicate that genes in this region show a close linkage with atopy, a sustained IgE response to allergens, and bronchial hyperreactivity (Kinet, J. P. et al. (1988) Proc. Natl. Acad. Sci. 85: 6483-6487; Adra, C. N. et al. (1994) Proc. Natl. Acad. Sci. 91: 10178-10182; and Sandford, A. J. et al. (1993) Lancet 341: 332-334).
The discovery of a new high affinity immunoglobulin E receptor-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of inflammatory responses.